To investigate the mechanism of esketamine (Esk) ameliorating postpartum depression (PPD)-like behaviors in mice by regulating the two pore domain potassium channel (TWIK)-related K⁺ channel 1(TREK-1) to activate the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, and to provide experimental evidence for clarifying the pathogenesis of PPD and developing novel targeted therapeutic strategies.

A total of 50 C57BL/6J pregnant mice were randomly divided into five groups (n=10 per group): control group, model group, experimental group, oe-NC group and oe-TREK-1 group. A PPD model was established in pregnant mice using the chronic unpredictable mild stress (CUMS) method. The control group was given an equal volume of normal saline; the model group was given normal saline after CUMS modeling; the experimental group was intraperitoneally injected with Esk (5 mg·kg^-1) once daily for 3 weeks after modeling; the oe-NC group was injected with lentivirus-encapsulated oe-NC by the tail vein before modeling and subsequent Esk administration; the oe-TREK-1 group was injected with lentivirus-encapsulated oe-TREK-1 by the tail vein before modeling and subsequent Esk administration. Depressive-like behaviors were evaluated using the sucrose preference test (SPT) and tail suspension test (TST). Hematoxylin-eosin (HE) staining and Nissl staining were used to observe the pathological morphology of hippocampal tissue; real-time fluorescent quantitative polymerase chain reaction and Western blotting were employed to detect the relative expression levels of TREK-1 in hippocampal tissue; enzyme-linked immunosorbent assay was utilized to measure the expression levels of serum sex hormones; immunohistochemistry was adopted to detect the expression of microglial marker proteins; Western blotting was used to determine the relative expression levels of endoplasmic reticulum stress-related proteins; immunofluorescence was applied to detect the relative expression levels of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB).

The sucrose preference rates in the control, model, experimental, oe-NC and oe-TREK-1 groups were (84.74±14.46)%, (19.08±2.86)%, (79.62±12.54)%, (80.15±11.38)% and (52.44±8.15)%, respectively; the immobility time ratios in the tail suspension test were (31.16±4.63)%, (75.38±14.62)%, (49.26±8.59)%, (48.97±7.82)% and (62.53±9.24)%, respectively; the relative expression levels of TREK-1 mRNA in the hippocampal tissues were 1.00±0.15, 2.87±0.45, 1.55±0.21, 1.56±0.19 and 2.18±0.36, respectively; the relative expression levels of TREK-1 protein were 1.00±0.16, 2.75±0.38, 1.86±0.27, 1.84±0.19 and 2.44±0.34, respectively; serum estradiol (E2) levels were (1 263.55±152.77), (638.16±78.32), (985.24±107.48), (981.67±106.34) and (752.33±116.45) pg·mL^-1, respectively; progesterone (P) levels were (9.53±1.06), (3.48±0.59), (8.54±1.07), (8.47±1.04) and (5.62±1.02) ng·mL^-1, respectively; prolactin (PRL) levels were (15.98±2.19), (29.31±4.62), (19.25±2.58), (19.88±2.67) and (23.47±3.46) ng·mL^-1, respectively; the relative expression levels of Iba-1 protein in the hippocampus were 1.00±0.16, 0.35±0.05, 0.87±0.14, 0.85±0.13 and 0.61±0.11, respectively; the relative expression levels of GRP78 protein were 1.00±0.17, 1.58±0.16, 1.17±0.14, 1.09±0.18 and 1.35±0.17, respectively; the relative expression levels of CHOP protein were 1.00±0.14, 1.71±0.23, 1.13±0.16, 1.11±0.12 and 1.34±0.18, respectively; the relative expression levels of Cleaved caspase-12 protein were 1.00±0.16, 1.45±0.19, 1.19±0.13, 1.16±0.12 and 1.38±0.16, respectively; the relative fluorescence intensities of BDNF were 1.00±0.16, 0.38±0.06, 0.84±0.09, 0.83±0.11 and 0.64±0.08, respectively; the relative fluorescence intensities of TrkB were 1.00±0.17, 0.57±0.09, 0.92±0.14, 0.91±0.12 and 0.75±0.11, respectively. Statistically significant differences were observed in the above indicators between the model group and the control group, between the experimental group and the model group, and between the oe-TREK-1 group and the oe-NC group (P<0.05, P<0.01, P<0.001).

Esketamine can alleviate PPD-like behaviors in mice by inhibiting TREK-1 expression, regulating sex hormone balance, improving microglial function and endoplasmic reticulum stress, and thereby activating the BDNF/TrkB pathway.